Depression and Antidepressants
Clinical depression is common, occurring in about one in five people during their lifetime and among the top four most common illnesses internationally as listed by the World Health Organization. The syndrome of depression may include persistent sadness, loss of self-esteem, difficulty concentrating, guilt, hopelessness, avoiding other people, loss of appetite, lack of enjoyment, and suicidal thoughts. Numerous conditions, diseases, and syndromes (e.g. anxiety disorders, post-traumatic stress, phobias, sleep disorders, fibromyalgia and other pain syndromes, migraine, enuresis, overactive bladder, anorexia and/or bulimia, obsessive-compulsive disorder, hair pulling, nail biting, teeth grinding etc.) exhibit symptoms of depression and are treated in part by anti-depressant agents. The following by way of example, is a brief summary of some of these disorders and current treatment modalities.
Post-Traumatic Stress Disorder
Post-traumatic stress disorder (PTSD) is an anxiety disorder that can develop following exposure to events that threaten or even cause physical harm. Some individuals experience a combination of both the threat of harm accompanied by physical harm. The response is an ongoing emotional reaction to the extreme psychological trauma caused by the stressors which overwhelm the individual's psychological defence mechanisms. Other terms for PSTS include railway spine, shell shock, battle fatigue, traumatic war neurosis or post-traumatic stress syndrome.
Events that may result in PTSD symptoms include assault, kidnapping, sexual assault, torture, prisoner of war, violent automobile accidents or receiving diagnosis of a life-threatening illness. Both children and adults experience PTSD. Children may experience this syndrome following sexually traumatic events such as age-inappropriate sexual experiences.
Typical symptoms include flashbacks and nightmares, avoidance of stimuli associated with the trauma, increased arousal such as difficulty falling or staying asleep, anger and hyper-vigilance. The symptoms unlike other types of syndromes persist, and may last more than six months resulting in significant impairment in social, family and work relationships.
Diagnostic criteria for PTSD are listed in Diagnostic and Statistical Manual of Mental Disorders IV and include the following: exposure to a traumatic event, persistent re-experience through nightmares or flashbacks, persistent avoidance of stimuli associated with the trauma including inability to discuss the event or other stimuli that may trigger flashbacks, persistent symptoms of increased arousal including difficulty sleeping, heightened anger and hyper-vigilance, symptoms lasting longer than one month, and impairment in social, work and relationships. Additionally, there are two criteria for a diagnosis of PTSD. The first requires that the person experienced, witnessed or confronted events involving actual or threatened serious injury or physical threat. The second is that the person's response involved intense fear, or helplessness.
Treatment typically involves various types of psychotherapy with some working better than others to reduce symptoms. Pharmacological strategies have reduced PTSD symptoms but have not been successful in eliminating them. These include antidepressants such as selective serotonin reuptake inhibitors (SSRI's) such as citalopram, escitalopram, fluvoxamine, paroxetine and sertraline, and tricyclic antidepressants (TCA's), which are associated with less efficacy and increased side-effects. Over-arousal symptoms may be alleviated using beta-blockers (e.g. propranolol), or alpha-adrenergic agonists (e.g. clonidine). These may block the effects of adrenaline on the amygdala. Other agents such as mood-stabilizers have been used including lithium, divalproex sodium, and carbamazepine and risperidone has been used to help with dissociation, mood and aggression. Some have tried combination therapies using a combination of psychotherapy (cognitive-behavioral therapy, group therapy, and exposure therapy are popular) and medications such as antidepressants, e.g. SSRI's, SNRI's (serotonin-norepinephrine reuptake inhibitors) such as venlafaxine, NaSSA's (noradrenergic and selective serotonergic uptake inhibitors) such as mirtazapine and tricyclic antidepressants such as amitriptyline or atypical antipsychotic drugs such as quetiapine and olanzapine.
Phobias
A phobia is generally described as an irrational and persistent fear of certain situations, activities, things, or people and occurs in about 8.7-18.1% of Americans (Kessler R C. et al., Arch. of Gen. Psych., 62; 617-27, 2005). If the fear is beyond one's control then one might be diagnosed with an anxiety disorder. Anxiety disorders such as social anxiety disorder, may be treated in part with the various antidepressant agents (e.g. escitalopram, fluvoxamine, paroxetine, sertraline, and venlafaxine) to relieve some symptoms; however, the efficacy is relatively low and there are associated-effects of the various agents (Hansen R A. et al., Int Clin Psychopharmacol. 23(3):170-9.2008).
Fibromyalgia and other Pain Syndromes
Fibromyalgia (fibromyositis and fibrositis) is a chronic disease occurring in approximately 2% of the population and is characterized by ongoing pain throughout the body, sleeping disturbances, and chronic exhaustion. While fibromyalgia may affect children, teenagers and males, the majority of sufferers are women between the ages of 20 and 50. The cause of fibromyalgia is unknown. Its development can appear after a traumatic experience (accident, emotional trauma, overworking, hormonal changes, sexual or physical abuse during childhood, or viral disease.) The disease has historically been considered either a musculoskeletal disease or neuropsychiatric condition; however studies have shown abnormalities within the central nervous system affecting brain regions that may be linked both to clinical symptoms.
Fibromyalgia symptoms include a combination of the following: non-restorative sleep leading to a feeling of chronic exhaustion, gastrointestinal problems (digestive tract spasms, constipation, diarrhea), headaches, migraines, increasing symptoms during stressful times, tendency to feel depressed or anxious, feeling of swelling or numbness, lack of concentration and memory loss and fatigue and muscle weakness. Regarding the neurological effects, patients often experience cognitive dysfunction (known as “brain fog” or “fibrofog”), characterized inability to concentrate difficulties with short and long-term memory, short-term memory consolidation, impaired speed of performance, inability to multi-task, cognitive overload, diminished attention span, anxiety and depressive symptoms.
Although, fibromyalgia is associated with polymorphisms of genes in the serotoninergic, dopaminergic and catecholaminergic systems these polymorphisms are not specific for fibromyalgia.
There is a proposal that the central abnormality responsible for symptoms associated with fibromyalgia is a disruption of normal dopamine-related neurotransmission. Dopamine is best known for its role in the pathology of schizophrenia, Parkinson's disease and addiction. Dopamine is thought to play a role in restless leg syndrome, commonly seen in fibromyalgia patients as well as in pain perception and natural analgesia. Thus, a reduction in the dopamine transmission system may be involved in this disease.
A reduction in dopamine synthesis has been reported in fibromyalgia patients assessed by positron emission tomography (PET) which demonstrated a reduction in dopamine synthesis in several brain regions in which dopamine plays a role in inhibiting pain perception, including the mesencephalon, thalamus, insular cortex and anterior cingulate cortex (Wood et al., J. Neurosci. 27: 5506-5514, 2007). Another study demonstrated that, whereas healthy individuals release dopamine into the caudate nucleus and putamen during a tonic experimental pain stimulus (i.e. hypertonic saline infusion into a muscle bed) (Scott D J, et al. J. Neurosci. 26 (42): 10789-95, 2006), fibromyalgia patients fail to release dopamine in response to pain and, in some cases, actually have a reduction in dopamine levels during painful stimulation (Wood P B. et al. J. Neurosci. 25 (12): 3576-82, 2007). Moreover, a substantial subset of fibromyalgia patients respond well in controlled trials to pramipexole, a dopamine agonist that selectively stimulates dopamine D2/D3 receptors and is used to treat both Parkinson's disease and restless leg syndrome (Holman A J. et al. Arthritis Rheum. 52 (8): 2495-505, 2005).
The diagnosis of fibromyalgia is done through a combination of observations. These include: presence of generalized pain lasting more than three months (above and below the waste and on the left and right side of the body and on the front and back of the body and pain when pressure is applied to at least 11 of 18 tender points.
While there is no generally accepted cure for fibromyalgia, several treatments have reduced symptoms, including medications, patient education, exercise and behavioral interventions.
Pharmacological treatments include non-steroidal anti-inflammatory agents, anti-depressants including TCAs, SSRIs and SNRIs, anti-seizure medications (e.g. gabapentin, pregabalin), and dopamine agonists (e.g. pramipexole, ropinirole). While none of these agents are curative, many such as the TCAs have unwanted side effects.
Anorexia Nervosa
Anorexia Nervosa (AN) is characterized by extreme concern about body weight and shape, severe self-imposed weight loss, and endocrine dysfunction. Body weight in these individuals through voluntary starvation, purging, excessive exercise, or other diet control methods including diet pills or diuretic drugs. Primarily, adolescent females are affected; however, about 10% of individuals with the diagnosis are male. Anorexia nervosa, can involve neurobiological, psychological, and sociological components, and can lead to death in certain circumstances.
The diagnostic criteria include the ICD-1-diagnostic criteria and the DSM-IV-TR criteria. According to the DSM-IV-TR criteria a person diagnosed with anorexia must show the following types of traits: Refusal to maintain body weight at or above a minimally normal weight for age and height (e.g., weight loss leading to maintenance of body weight less than 85% of that expected; or failure to make expected weight gain during period of growth, leading to body weight less than 85% of that expected); intense fear of gaining weight or becoming obese; disturbance in the way in which one's body weight or shape is experienced, undue influence of body weight or shape on self-evaluation, or denial of the seriousness of the current low body weight; absence of at least three consecutive menstrual cycles (amenorrhea) in women who have had their first menstrual period but have not yet gone through menopause (postmenarcheal, premenopausal).
Treatments for anorexia involve behavioural therapy as well as pharmacological methods. Pharmacological methods have included SSRIs or other antidepressant medications but these have not been found to be generally effective for either treating anorexia (Claudino A M., et al. Cochrane Database Syst Rev, 1, CD004365, 2006) or preventing relapse (Walsh B T., et. al., AMA, 295(22), 2605-12, 2006).
Anorexia may be linked to a disturbed serotonin system, especially areas of the brain with 5HT1A (Kaye W H, et al., Physiol Behav, 86(1-2), 15-7. 2005. This system is linked to anxiety, mood and impulse control. Other hypotheses involve modulation of the dopamine signaling pathway. For example, the hypothalamus is important in integrating various hormonal and neuronal signals to regulate appetite and metabolism and thereby serves in the homeostasis of body weight regulation. Additional neural circuits superimposed on this system have the potential to override the homeostatic signals, resulting in either gluttony or anorexia at the extremes. Midbrain dopamine neurons have long been implicated in mediating reward behavior and the motivational aspects of feeding behavior. Recent results reveal that hormones implicated in regulating the homeostatic system also impinge directly on dopamine neurons. For example, leptin and insulin directly inhibit dopamine neurons, whereas ghrelin activates them (Palmiter R D., Trends Neurosci. 30(8):375-81, 2007). Some have suggested an over active dopaminergic system may lead to hyperactivity associated with eating disorders and that antagonism to the system may improve conditions such as anorexia (Verhagen L A. et al., Eur Neuropsychopharmacol. Oct. 30[Epub ahead of print], 2008); however, to date significant strides have not been made in the treatment of these individuals.
As evident from this summary, there are numerous diseases, syndromes or conditions with depression-related symptoms that are treated with anti-depressant agents and many of these conditions have attributes that are related to changes in the dopaminergic system.
Types of Antidepressants and their Mechanisms of Action
There are many types of antidepressants used in clinical practice. The various types of antidepressant drugs can be grouped according to basic mechanisms of action, including the following:                1. Antidepressants that mainly inhibit neuronal reuptake of norepinephrine (noradrenaline) and to a lesser extent inhibit neuronal reuptake of dopamine and serotonin.        2. Antidepressants that inhibit the neuronal reuptake of serotonin (SSRI)        3. Antidepressants that inhibit the neuronal reuptake of dopamine.        4. Antidepressants that inhibit the neuronal reuptake of both norepinephrine and serotonin.        5. Antidepressants that inhibit the serotonin type-2 receptor.        6. Antidepressants that inhibit monoamine oxidase.        7. Antidepressants that stimulate adrenoceptors or dopamine receptors directly.        8. Mood stabilizers/preventatives.        9. Antipsychotics used for psychosis but which may treat the depression within the psychotic illness.        10. Vilazodone-type combined mechanism of SSRI and 5HT1A stimulation.        
Based on the above mechanisms, antidepressants include a number of distinct classes of compounds acting at the level of the receptor. Selective serotonin reuptake inhibitors (SSRI's) are thought to prevent reuptake of serotonin by the presynaptic nerve, thus maintaining higher levels of 5-HT at the synapse. Examples of these agents include: fluoxetine (Prozac), paroxetine (Paxil), escitalopram (Lexapro, Esipram), citalopram (Celexa), and sertraline (Zoloft). Serotonin-norepinephrine reuptake inhibitors (SNRI's) have effects on both norepinephrine and 5-HT and include: venlafaxine (Effexor) and duloxetine (Cymbalta). Noradrenergic and specific serotonergic antidepressants are thought to increase norepinephrine and serotonin transmission by blocking pre-synaptic α-2 adrenergic receptors. One agent in this class is mirtazapine (Avanza, Zispin, Remeron). Norepinephrine reuptake inhibitors (NRI's) prevent reuptake of norepinephrine by presynaptic neurons and includes reboxetine (Edronax). Norepinephrine-dopamine reuptake inhibitors, including bupropion (Wellbutrin, Zyban), inhibit reuptake of norepinephine and dopamine. Tricyclic antidepressants (TCA's) block the reuptake of norepinephrine and serotonin and include amitriptyline and desipramine. Monoamine oxidase inhibitors (MAOI's) block the enzyme, monoamine oxidase, which breaks down the neurotransmitters dopamine, serotonin, and norepinephrine (noradrenaline). An example includes phenelzine (Nardil).
Adverse Reactions Associated with Antidepressant Therapies
Currently-available drugs for treating depression have delayed onset of action, poor efficacy, anticholinergic effects at therapeutic doses, cardiotoxicity, convulsions and the clinical risk of overdosing. In particular, side effects of SSRI's include nausea, diarrhoea, headaches and sexual dysfunction such as loss of libido, failure to reach orgasm and erectile problems. Serotonin syndrome is also associated with the use of SSRI's. The Food and Drug Administration has included Black Box warnings on all SSRI's stating that they double the potential for suicide (from 2 in 1,000 to 4 in 1,000) in children and adolescents who are prescribed these drugs. Side effects of TCA's include dry mouth, blurred vision, drowsiness, dizziness, tremors, sexual problems, skin rash, and weight gain or loss. Side effects of MAOI's include some more uncommon but serious ones such as liver inflammation, heart attack, stroke, and seizures. MAOI's are of particular concern because there are potentially fatal interactions between this class of medication and certain foods (those containing tyramine). Furthermore, a large number of clinically depressed individuals remain refractory to currently-available therapies and the effects of therapies wane over time. These concerns point to the need for new, less adverse approaches to treat affective disorders such as depression.
Use of Antipsychotics for the Treatment of Depression
Although the use of antipsychotics for depression has been controversial (M. Robertson and M. R. Trimble, J. Affective Disorders 4: 173-193, 1982), amoxapine (Asendin®) and trazodone (Desyrel®) have been suggested to have effects on both types of illnesses, depression and psychosis (R. Apiquian et al., Schizophr. Res. 59: 35-39, 2003). Robertson and Trimble summarized studies showing that thioridazine, chlorpromazine, perphenazine, fluphenazine, thiothixene, flupenthixol, and chlorprothixene are as effective as imipramine, amitriptyline, or doxepin in treating depression, especially within the context of psychosis or schizophrenia. However, the doses of these antipsychotics are generally lower in treating depression, and it is likely that the antipsychotics are actually only removing the element of anxiety within the clinical depression as opposed to treating true clinical depression (M. M. Katz et al., Depression & Anxiety 4: 257-267, 1996-97).
More recently, reviews have summarized that low doses of the atypical antipsychotic amisulpride (50-100 mg/day) or levo-sulpiride (50-150 mg/day) are effective in dysythmia, a mild chronic form of depression, while higher doses (˜100-400 mg/day) are effective against psychosis (L. Pani & G. L. Gessa, Mol. Psychiat. 7: 247-253, 2002; A. Mucci et al. Pharmacol. Res. 31: 95-101, 1995). However, amisulpride has not been approved for depression. Nor have these compounds been suggested for more severe forms of depression.
The antipsychotic doses of S-amisulpride and S-sulpiride are related to their dissociation constants at the dopamine D2 receptor, with that for S-amisulpride being 1.8 nM and that for S-sulpiride being 9.9 nM (P. Seeman. Canad. J. Psychiat. 47: 27-38, 2002). Amisulpride is a second-generation (atypical) antipsychotic, a substituted benzamide. It appears to be an effective agent in treating schizophrenia for what are characterized as positive and negative symptoms. The recommended doses are between 400 mg/day and 800 mg/day. Amisulpride demonstrates a good global safety profile, particularly when compared with first-generation antipsychotics, such as haloperidol. Studies point towards amisulpride's antidepressant effect in dysthymia and possibly treating affective psychosis and chronic fatigue syndrome (Green B. et al. Curr Med Res Opin. 18(3):113-7, 2002); however, the mechanism of this action is not established.
Haloperidol
As opposed to amisulpride, haloperidol is a first generation “typical” antipsychotic agent and has not been considered for treatment of depression or depression-type symptomology that occurs with other conditions, syndromes or diseases. Associated with this class of agents are many side-effects. Using the customary daily doses of 5 to 20 mg of oral haloperidol per day on a long-term basis, the following are such side effects. Cardiovascular effects include: tachycardia, hypotension, and hypertension, QT prolongation and/or ventricular arrhythmias, ECG patterns indicating torsade de pointes, and sudden and unexpected death. Central nervous system effects include extrapyramidal signs (EPS) such as Parkinson-like signs, akathisia or dystonia (including opisthotonos and oculogyric crises), tardive dyskinesia and tardive dystonia. The following are other central nervous system effects associated with the use of standard antipsychotic doses of haloperidol: insomnia, restlessness, anxiety, euphoria, agitation, drowsiness,depression, lethargy, headache, confusion, vertigo, and grand mal seizures. Neuroleptic malignant syndrome (NMS), hyperpyrexia and heat stroke have been reported with haloperidol.
The following is a current list of indications for the use of haloperidol: acute psychosis, such as drug-induced psychosis (LSD, amphetamines, phencyclidine), acute mania, hyperactivity, aggression, agitation and confusion associated with cerebral sclerosis, adjunctive treatment of alcohol and opioid withdrawal, treatment of neurological disorders such as tics, Tourette syndrome, and chorea, treatment of severe nausea/emesis (postoperative, side-effects of radiation and cancer chemotherapy), adjunctive treatment of severe chronic pain, always together with analgesics, personality disorders such as borderline personality disorders and in the treatment of intractable hiccups.
Animal Models of Depression
There are a limited number of animal models of depression (S. Kapur & J. J. Mann, Biol. Psychiat. 32: 1-17, 1992) and as with most animal models, their applicability to humans is in question. Nevertheless, there are four types of such models which have been used in the development of antidepressant agents.
1. The “learned helplessness” model, where animals are exposed to inescapable stressors such as to decrease spontaneous activity and decrease the effort to escape, effects which are reversed by imipramine, desipramine, amitryptiline, doxepin, iprindole, mianserin, iproniazid and pargyline or by electroshock (A. D. Sherman et al., Pharmacol. Biochem. Behay. 16: 449-454, 1982).
2. The “forced swim test” or “behavioral despair” is where rats are forced to swim in a limited space. After some hopeless attempts at escape, the rats become immobile, an effect which some antidepressants may reverse.
The relevance of these two animal “frustration” models to clinical depression has been questioned (P. Willner, Psychopharmacology 83: 1-16, 1984).
3. There are many types of rat behavior tests for motivation and reward. Although dopamine release is central to these behaviors, and antidepressants may have effects on such tests, the clinical relevance of such tests to human depression has been questioned (Refs. In S. Kapur & J. J. Mann, Biol. Psychiat. 32: 1-17, 1992).
4. While not a behavioral test, a consistent and reliable index of antidepressant action is the reduction in the density of beta-adrenoceptors in the rat cortex after 10 days or two weeks of antidepressant treatment, with the single exception of serotonin-selective uptake inhibitors. This effect holds not only for the various classes of antidepressants listed above, but also for other types of antidepressant treatment, such as nitric oxide synthase inhibitors (B. Karolewicz et al., Eur. J. Pharmacol. 215-220, 1999).
Role of Dopamine in Depression is shown by Antipsychotic Block of Antidepressants
The following study is one example indicating a role for dopamine in depression. Using the behavioral despair test (forced swimming test) in mice, it was shown that apigenin significantly decreased the duration of immobility in the forced swimming test in mice, an indicator of an antidepressant effect. The authors showed that apigenin attenuated the forced swim test-induced decrease of DA turnover in the amygdala and increase of DA turnover in the hypothalamus. A relatively high dose of haloperidol (0.2 mg/kg), a dopamine D2 receptor antagonist, blocked the apigenin-induced decrease in immobility in the forced swimming test. These results suggested that the antidepressant properties of apigenin may involve dopamine (T. Nakazawa et al. Biol. Pharm. Bull., 26(4):474-80, 2003).
Antipsychotic agents differ in their efficacy on depression, depending on the clinical features and the drug dosage used. For example, one study examined the ability of various antipsychotics to treat the depressive symptoms in acute exacerbations of schizophrenia. As noted above, these effects may indicate a drug effect on reducing anxiety, rather than clinical depression. However, the finding suggested that there is a differential effect of various antipsychotic agents on these depressive symptoms. For example, amisulpride was better than haloperidol. The Brief Psychiatric Rating Scale (BPRS) anxiety/depression subscore found amisulpride (400-800 mg/day)(5.6±6.1) to be significantly better (P=0.011) than haloperidol (15-20 mg/day) (4.4±5.5) or risperidone (8 mg/day)(3.7±4.7). (J. Peuskens et al. Eur Neuropsychopharmacol., 12(4):305-10, 2002).
These data suggest that not all antipsychotics or doses will be useful for inhibiting depressive symptoms. Moreover, the depression component in schizophrenia patients, exemplified above, may respond differently than endogenous depression that is not associated with schizophrenia or psychosis.
In addition, it is known that there are fundamental differences between antipsychotics based on their differing affinities for the dopamine D2 receptor. For example, traditional antipsychotics such as haloperidol and chlorpromazine bind tightly to the dopamine D2 receptor (P. Seeman et al., Am J. Psychiatry. 156:876-884, 1999), while the newer or atypical antipsychotic agents such as quetiapine, clozapine and amisulpride rapidly dissociate from the D2 receptor (P. Seeman et al., Can. J. Psychiatry 47:27-38, 1995).
A review of atypical antipsychotics for enhancing antidepressant action in major depression revealed that while small clinical studies appeared to show some improvement, large well-controlled clinical studies failed to show effectiveness of atypical antipsychotics in reducing major depressive disorder when used with antidepressant agents (Shelton R C et al. Acta. Psychiatr. Scand. (Jan 8 epub ahead of print, 2008).
Role of Dopamine in Cognition
It is known that there is a vast array of medications alleged to improve cognition. Such compounds include, for example, the following: modafinil (R. E. Morgan et al., Pharmacol. Biochem. Behay. 86: 531-541, 2007), rimonabant, donepezil (L. Wise et al., Neuropsychopharmacol. 32:1805-1812, 2007), various herbs (D. Kennedy, A. Scholey, Curr. Pharm. Des. 12: 4613-4623, 2006), nicotinic partial agonists (G. Dunbar et al., J. Clin. Pharmacol. 46: 715-726, 2006), memantine (D. R. Guay, Consult. Pharm. 18: 625-634, 2003), Ginkgo biloba (M. Zhang, J. Cai, Behay. Pharmacol. 16: 651-656, 2005), Norepinephrine uptake inhibitor (atomoxetine) (E. Tzavara et al., Mol. Psych. 11:187-195, 2006), D2 receptor agonist bromocriptine (R. Cools et al., J. Neurosci. 27: 5506-5514, 2007), cycloserine (J. E. Bailey et al., Psychopharmacology 193: 579-585, 2007), ampakines (Cortex pharmaceuticals), and caffeine.
There are many components to cognition, including overall long-term memory, working memory, performance ability, motivation, alertness, mood, attention and distractibility, to mention just a few. While each of the compounds and medications listed above may improve one or two of the components of cognition, there is no single compound that improves all aspects and components of cognition.
Moreover, each of these compounds has adverse effects. For example, nicotinic agonists elicit dizziness, headache, and many other somatic signs and symptoms, while memantine can cause depression, insomnia, akathisia, agitation, dizziness, drowsiness, restlessness and hyper-excitability (D. R. Guay, Consult. Pharm. 18: 625-634, 2003).
Of the many components constituting the overall cognitive process, the features of attention, motivation and mood are central. That is, an individual who is not motivated, not attentive, and in a depressed mood, would not score high on any scale of cognition.
Role of Dopamine in other Diseases, Syndromes or Conditions
It should be noted that a role for dopamine has been shown for other diseases, syndromes or conditions which have typically been treated with anti-depressant agents including anxiety disorders (Schreier F R., et al. Depress Anxiety. Epub Jan. 2009), post-traumatic stress (Noble E P., Am J Med Genet B Neuropsychiatr Genet. 1;116B(1):103-25; 2003), sleep (Monti J M., Sleep Med Rev. Apr;11(2):113-33. Epub Feb, 2007), fibromyalgia and other pain syndromes (Wood et al., J. Neurosci. 27: 5506-5514, 2007), migraine (Cologno D. et al., Neurol Sci., May;29 Suppl 1:S166-8, 2008), enuresis and urinary incontinence (Ambrosini P J., J Clin Psychopharmacol. Oct;4(5):247-53, 1984), anorexia (Palmiter R D., Trends Neurosci. 30(8):375-81, 2007) and bulimia (Capasso A., et al. Rev Recent Clin Trials. Jan;4(1):63-9, 2009).